Takahide Taguchi

Concurrent chemoradiotherapy with cisplatin, 5-fluorouracil, methotrexate, and leucovorin in patients with advanced resectable squamous cell carcinoma of the larynx and hypopharynx.

Conclusions. This regimen of concurrent chemoradiotherapy was safe and well tolerated. In terms of larynx preservation, the present regimen appears to be useful for patients with advanced resectable squamous cell carcinoma (SCC) of the larynx and hypopharynx. Objectives. To evaluate the efficacy and toxicity of concurrent chemoradiotherapy in patients with advanced resectable SCC of the larynx and hypopharynx, and to demonstrate the feasibility of larynx preservation. Patients and methods. Forty-six eligible patients were treated. The chemotherapy regimen consisted of a combination of four drugs: cisplatin (60 mg/m2, day 4), 5-fluorouracil (5-FU) (600 mg/m2 given continuously for 120 h, days 1–5), methotrexate (MTX) (30 mg/m2, day 1), and leucovorin (LV) (20 mg/m2, days 1–5). Two cycles of this regimen were given every 4 weeks during radiotherapy. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8–2.0 Gray, to a total dose of 66.6–70.2 Gray. Results. The 3-year disease-specific survival rates of patients with laryngeal or hypopharyngeal SCC were 81.3% and 78%, respectively. The 3-year disease-specific survival rates with larynx preservation of patients with laryngeal or hypopharyngeal SCC were 46.7% and 59%, respectively. The main toxicities were neutropenia, dermatitis, mucositis, and infection.

Restoration of BRAK / CXCL14 gene expression by gefitinib is associated with antitumor efficacy of the drug in head and neck squamous cell carcinoma.

Clinical efficacy of gefitinib (ZD1839, Iressa), which is an inhibitor specific for epidermal growth factor (EGF) receptor tyrosine kinase, has been shown in non‐small‐cell lung carcinoma patients with EGF receptor mutations, so these mutations are useful marker(s) to find a responder for the drug. Recent studies have shown that the EGF receptor gene mutation is rare in squamous cell carcinoma in the esophageal and head and neck regions. We previously reported that the expression of the chemokine BRAK/CXCL14 in head and neck squamous cell carcinoma (HNSCC) cells was down‐regulated by EGF treatment, and that forced expression of BRAK in tumor cells decreased the tumorigenicity of the cells in xenografts. Thus, we investigated the relationship between restoration of BRAK expression by gefitinib and the efficacy of the drug for tumor suppression. We found that EGF down‐regulated BRAK expression through the MEK–extracellular signal regulated kinase pathway and that this down‐regulated expression was restored by gefitinib in vitro. Oral administration of gefitinib significantly (P < 0.001) reduced tumor growth of xenografts of three HNSCC cell lines (HSC‐2, HSC‐3, and HSC‐4), in female athymic nude mice, accompanied by an increase in BRAK expression specifically in tumor tissue. This tumor‐suppressing effect of the drug was not observed in the case of BRAK non‐expressing cells. Furthermore introduction of BRAK shRNA vector reduced both the expression levels of BRAK in HSC‐3 cells and the antitumor efficacy of gefitinib in vivo. Our data showing an inverse relationship between BRAK expression levels in tumor cells and the tumor growth rate indicate that the gefitinib‐induced increase in BRAK expression is beneficial for tumor suppression in vivo. (Cancer Sci 2009)

Platinum-based Chemotherapy Plus Cetuximab for the First-line Treatment of Japanese Patients with Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck: Results of a Phase II Trial

Objective To assess the efficacy and safety of cetuximab in combination with cisplatin and 5-fluorouracil for first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Methods In this open-label, single-arm, multicenter, Phase II study conducted in Japan, patients with confirmed recurrent and/or metastatic squamous cell carcinoma of the head and neck received weekly cetuximab (week 1, 400 mg/m2; subsequent weeks, 250 mg/m2) plus a maximum of six three-weekly cycles of cisplatin (100 mg/m2, day 1) and 5-fluorouracil (1000 mg/m2/day, 24-h infusion, days 1–4). The primary endpoint was the best overall response assessed by an independent review committee according to the modified World Health Organization criteria. Results In total, 33 patients received treatment. The most frequent primary tumor site was the hypopharynx (42%), and most patients had metastatic disease (85%). The best overall response rate as assessed by the independent review committee was 36% (95% confidence interval: 20, 55) and was significantly greater (P = 0.002) than the protocol-specified threshold of 15% at the one-sided 5% level. The disease control rate was 88%. The median progression-free survival and overall survival were 4.1 and 14.1 months, respectively. There were no unexpected safety concerns. Grade 3 or 4 adverse events were experienced by nearly all patients (32, 97%). No adverse events were fatal. Conclusions The demonstrated efficacy and safety of cetuximab in combination with cisplatin and 5-fluorouracil for the first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck justify the further use of this combination treatment in this patient population (ClinicalTrials.gov number, NCT00971932).

Role of 18F-FDG PET in detecting primary site in the patient with primary unknown carcinoma

The aim of this study was to verify the effectiveness of positron emission tomography (PET) in detecting primary sites in carcinoma of unknown primary (CUP) patients. In this study, CUP represented a group of heterogeneous tumors that shared the clinical manifestation of metastatic carcinoma with no obvious primary site at the time of first diagnosis, which included clinical investigations, computed tomography, magnetic resonance imaging and panendoscopy. We reviewed the records of 24 patients with CUP between January 1995 and December 2009. The patients who demonstrated additional tracer uptake sites other than previously known metastatic lesions by PET scan were done direct biopsies for the sites of accumulation. Patients who had a negative PET scan or for whom the primary site could not be identified by direct biopsies underwent examination under anesthesia of the at-risk occult tumor sites. PET scan demonstrated focal accumulation suspicious for primary tumor in 12 (50.0%) of 24 patients: tonsil 5, nasopharynx 3, hypopharynx 1, tongue 1, larynx 1, and maxillary sinus 1. A subsequent biopsy of these sites revealed primary cancer in 9 (37.5%) of 24 patients: tonsil 5, nasopharynx 1, hypopharynx 1, tongue 1, and maxillary sinus 1. In the remaining three patients, no malignant cells were found by the biopsy of the accumulated area: nasopharynx 2, larynx 1. PET scans increase the yield of primary tumor by 37.5%. The sensitivity, specificity for PET scan were 80.8, 76.9%, respectively. PET scanning is useful in detecting primary cancer of CUP patients.

Correlation between FDG-PET findings and GLUT1 expression in salivary gland pleomorphic adenomas

ObjectiveOne reason for the difficulty in accurate preoperative pathological diagnosis of major salivary gland tumors with fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) is the tendency of pleomorphic adenomas to have a high, standardized uptake value (SUV). The expression of glucose transporter 1 (GLUT1) and the quantity of GLUT1 messenger RNA (mRNA) were analyzed in specimens of pleomorphic adenoma to identify whether GLUT1 is responsible for the increased glucose uptake in FDG-PET examinations of these tumors.MethodsEighty salivary gland tumors resected at Yokohama City University Hospital were retrospectively investigated. FDG-PET was performed prior to surgery. PET images were evaluated by two experienced radiologists. GLUT1 was immunohistochemically stained, and GLUT1 mRNA density was quantified using real-time polymerase chain reaction in 10 of 40 pleomorphic adenomas.ResultsThe pleomorphic adenomas stained positively for GLUT1, and there was significant correlation between the GLUT1 index and the SUV in FDG-PET.ConclusionsGLUT1 is expressed in salivary gland pleomorphic adenomas. Furthermore, the GLUT1 index shows significant correlation with the SUV of FDGPET. This result suggests that GLUT1 plays an important role in increasing FDG uptake in salivary gland pleomorphic adenomas.

Phase I trial of combined chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for patients with locally advanced squamous cell carcinoma of the head and neck.

BackgroundThis phase I study was designed to determine the maximum tolerated dose (MTD) and toxicities of combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).MethodsPatients received two cycles of chemotherapy repeated every 4 weeks. Starting doses (dose level 0) were: docetaxel 60 mg/m2, cisplatin 60 mg/m2, and 5-day continuous infusion 5-FU 600 mg/m2 per day. At least three patients were examined at each dose level before advancing to the next level.ResultsNineteen male patients (median age, 59.5 years) were enrolled. Eighteen patients had previously untreated stage III or IV SCCHN and 1 had local relapse, rT4. In the 19 patients, the regimen was well tolerated, with neutropenia as the most common toxicity (grade 3; n = 11; grade 4; n = 1). Dose-limiting toxicity (DLT) was observed at the fifth dose level (docetaxel 70 mg/m2, cisplatin 70 mg/m2, 5-FU 750 mg/m2 per day), when 1 patient developed grade 2 renal toxicity during the first course; another 2 patients had persistent neutropenia. These doses were thus deemed the MTD for the regimen. In the 18 assessable patients, the overall clinical response rate was 94% (17/18 patients) and primary-site complete response (CR) occurred in 4 (22%) patients.ConclusionThe MTD of this regimen was docetaxel 70 mg/m2 on day 1, cisplatin 70 mg/m2 on day 4, and 5-FU 750 mg/m2 per day for 5 days. The regimen was safe and generally well-tolerated and demonstrated good efficacy in patients with locally advanced SCCHN.

The efficacy and safety of concurrent chemoradiotherapy for maxillary sinus squamous cell carcinoma patients

OBJECTIVE Combined treatment modality, e.g., definitive surgery followed by radiotherapy (RT) and definitive RT with concurrent chemotherapy, has been applied for advanced maxillary sinus squamous cell carcinoma (MSSCC) patients to obtain a better survival with organ preservation in Japan. METHODS The outcome of 40 patients with MSSCC between 1991 and 2007 in our institute was analyzed retrospectively. There were 36 males and 4 females, the average age being 59.5 years (ranging from 34 to 81 years). The median follow-up time was 66.1 months. All the patients had received a combined treatment consisting of definitive surgery, RT, and intra-arterial or systemic chemotherapy. The chemotherapeutic regimen was different depending on the performance status and/or complications of the patients. Since 1998, concurrent chemoradiotherapy with cisplatin, 5-fluorouracil, methotrexate and leucovorin regimen (CCRT-PFML) instead of neo-adjuvant chemotherapy has been applied. RESULTS The overall 5-year survival rate was 59.2%, the 5-year disease-specific survival rate was 71.7%, and the 5-year organ preservation survival rate was 42.4%. In the group receiving CCRT-PFML, the overall 5-year survival rate was 60.0%, the 5-year disease-specific survival rate was 76.0%, and the 5-year organ preservation survival rate was 60.3%. CONCLUSION CCRT-PFML for advanced MSSCC patients is feasible to preserve the organs without reducing the survival rate.

Predictive and Prognostic Value of Metabolic Tumor Volume (MTV) in Patients with Laryngeal Carcinoma Treated by Radiotherapy (RT) / Concurrent Chemoradiotherapy (CCRT)

Purpose To evaluate the predictive and prognostic value of pretreatment metabolic tumor volume (MTV) in patients with treated by radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). Methods We reviewed the records of 118 patients with newly diagnosed laryngeal carcinoma, who had been treated by RT or CCRT. Pretreatment positron emission tomography (PET) was performed, and MTV values were obtained by contouring margins of standardized uptake value. Clinical factors and MTV were analyzed for their association with survival. Results Patients with residual disease showed a significantly higher MTV than those with a complete response (CR) after primary treatment. Univariate analysis showed that the patients with a high MTV had a significantly lower disease-free survival (DFS) (p < 0.001). Subsite (p = 0.010), T-stage (p < 0.001), nodal metastasis (p < 0.001) and clinical stage (p < 0.001) also correlated significantly with DFS. In the multivariate analysis, MTV and clinical stage were both found to be independent prognostic factors for DFS (p = 0.001, p = 0.034, respectively). The 3-year DFS for patients with a high MTV were significantly poorer than those with a low MTV (p < 0.001). Conclusions MTV of the primary tumor is a significant prognostic factor for DFS in patients with laryngeal carcinoma treated by RT or CCRT. The results imply that MTV could be an important factor when planning treatment and follow-up for patients with laryngeal carcinoma.

Randomized Phase III Trial of Adjuvant Chemotherapy with S-1 after Curative Treatment in Patients with Squamous-Cell Carcinoma of the Head and Neck (ACTS-HNC)

Background We conducted a phase III study to evaluate S-1 as compared with UFT as control in patients after curative therapy for stage III, IVA, or IVB squamous-cell carcinoma of the head and neck (SCCHN). Patients and Methods Patients were randomly assigned to the UFT group (300 or 400 mg day-1 for 1 year) or the S-1 group (80, 100, or 120 mg day-1 for 1 year). The primary end point was disease-free survival (DFS). Secondary end points were relapse-free survival, overall survival (OS), and safety. Results A total of 526 patients were enrolled, and 505 were eligible for analysis. The 3-year DFS rate was 60.0% in the UFT group and 64.1% in the S-1 group (HR, 0.87; 95%CI, 0.66-1.16; p = 0.34). The 3-year OS rate was 75.8% and 82.9%, respectively (HR, 0.64; 95% CI, 0.44-0.94; p = 0.022). Among grade 3 or higher adverse events, the incidences of leukopenia (5.2%), neutropenia (3.6%), thrombocytopenia (2.0%), and mucositis/stomatitis (2.4%) were significantly higher in the S-1 group. Conclusions Although DFS did not differ significantly between the groups, OS was significantly better in the S-1 group than in the UFT group. S-1 is considered a treatment option after curative therapy for stage III, IVA, IVB SCCHN. Trial Registration ClinicalTrials.gov NCT00336947 http://clinicaltrials.gov/show/NCT00336947

Decrease of creatinine clearance rate with aging in patients with head and neck cancer in Japan

BackgroundWe aimed to clarify the reason for the lower dosage of cis-platinum (CDDP) in patients with head and neck cancer in Japan compared with that in other countries, by evaluating renal function.MethodsWe studied 375 patients with head and neck cancer who had been hospitalized from January 1998 to October 2005, to evaluate and treat the disease. The creatinine clearance rate (Ccr) was calculated at least three times before beginning the treatments, and the average Ccr was estimated to evaluate the renal function.ResultsThe Ccr decreased with aging, and the percentages of patients with Ccr lower than 65 ml/min per 1.73 m2 were 27.1% of patients in their fifties, 36.8% in their sixties, 62.3% in their seventies, and 87.5% in their eighties. There was no correlation between renal function and the Japanese lifestyle (i.e., diet. water consumption).ConclusionThe renal function of Japanese decreases rapidly with aging, whereas that of Americans is maintained for longer periods. The poor renal function of Japanese is one of the causes of the need to reduce the dosage of or avoid the administration of CDDP in cancer patients.